Ever since mankind came into this world, it has been relentlessly assaulted and challenged and terrorized by the multitudes of infections diseases that have since become a part of our lives. History itself offers ghastly stories of vicious disease. For example, half the population of Athens succumbed to plague in the year 430 BCE. Another plague - perhaps smallpox - swept through the Roman Empire at around 165 CE, claiming the lives of four to seven million people. That was not the last time Europe suffered a plague attack. About a millennium later, in the 1340s, a scourge descended upon India and China, killing 9 out of every 10 people, before making its way to Europe, and later, Moscow and North Africa.

Mankind was never safe from the threat of pestilence. In those days before drug therapy was properly developed, infection was as good as a death sentence. People who contracted consumption waited around for death’s hammer to strike. Houses sheltering victims of the bubonic plague were boarded up, both patients and healthy people left to die inside. And medical treatment, without benefit of science, did far more harm than good, and hardly hampered the imminent spread of disease.

All of this changed in the 1920s when Alexander Fleming, a Scottish bacteriologist doing research at St. Mary’s Hospital in London, discovered the world’s first antibiotic, penicillin¹. A plate of staphylococci he had been cultivating had been contaminated with mould², which he found to be killing off the bacteria surrounding it. Realizing the potential of penicillin as a weapon against infectious disease, a team of British scientists at Oxford University, led by Howard Florey, pushed penicillin research forward. By the end of World War II, penicillin was available to everyone, and had saved more soldiers than the war had claimed. Scientists eagerly began to look for other antibiotics-producing organisms. Mortality rates dropped drastically. Infectious diseases caused by bacteria were stopped in their tracks. Antibiotics had become the saviour of mankind.

Today, penicillin is ineffective against many of the diseases it had successfully combated sixty years ago. Some microorganisms such as Staphylococcus are resistant to three, maybe four different types of antibiotics, or maybe more. Diseases we thought would never plague the developed world again, such as the White Plague (tuberculosis), are back on the rise. And every day there is another bacteria somewhere becoming resistant to antibiotics. The shield that antibiotics has erected to separate us from the dangers of disease is suddenly gone. We are no longer safe.

To understand all this, you need to know how nature works. Evolution has always favoured the fittest in any contest for survival. In the presence of selection (in this case, antibiotics), mutant microorganisms that are resistant are given the opportunity to flourish as their sensitive counterparts are wiped out by medicine. Mutant microorganisms that may be dangerous and had caused the disease in the first place, or harmless ones that had inhabited our bodies ever since we were born into the world. The friendly ones become hostile, the hostile ones become even more aggressive. And all of this has one factor in common: man.

Look around you and see the horrors of antibiotics misuse. People who fail to finish their course of antibiotics treatment actually encourage this phenomenon; those who abuse antibiotics usage by consuming them as prophylactics or use them in agriculture to promote animal growth and prevent disease³ only worsen the situation in the long run. And then there’s the consumer market: antibacterial paint, antibacterial soap, antibacterial mattresses. It’s a wonder that all the bacterial of the world have not yet turned against us.

But even then mankind has been cushioning itself from the truth, claiming that even if a certain bacteria became resistant to a certain antibiotic, well, so what? Resistance is caused by certain mutations in the bacteria’s genome, and everybody knows that the frequency of mutations actually doing any good is so low as to be insignificant. And anyway, we have so many different types of antibiotics that even if a bacteria cannot be killed off by one, we’ll still have an arsenal against it. Before the bacteria has accumulated resistance to more of these drugs, we’ll have wiped it out with others!

However, this reasoning was shattered in 1963 when Dr. Tsutomo Watanabe announced this to the world: bacteria can gain resistance to one, two, three, four (!) different antibiotics AT ONE GO just by socializing with other bacteria ⁴. And because bacteria are promiscuous, this is not just restricted to members of the same species.

You have to give these bacteria some credit. Although they have only one chromosome that carries genes coding for material that ensure their survival and growth, bacteria can also have any number of free-floating closed circular DNA called plasmids. These are probably not native to a bacterial cell, but are picked up from the environment, and can replicate along with the bacterial chromosome. They do not carry some genes needed by the bacteria under all conditions, but may contain information for (among other things) physiological function, virulence and, most importantly, resistance to antibiotics. These plasmids may be transferred from one bacteria to another by conjugation⁵. Alternatively, a replicating bacterial cell may pass on these plasmids to its daughter cells. These plasmids can either remain as extrachromosomal matter, or integrate itself into the bacterial chromosome. Also, Dr. Barbara McClintock’s discovery of ‘jumping genes’ or transposons⁶ led to the discovery that certain bacterial genes could jump from one region of its chromosome to another, and between bacterial cells. And if you thought that was bad, perhaps you should also consider the fact that certain microbes can also easily absorb DNA from the environment - DNA left behind by a ruptured cell, perhaps.

Think of the implications. Many different plasmids, maybe each one carrying a resistance gene to a different antibiotic - all being transferred from one bacteria at one go. And many, many different species and families of bacteria out there exchanging genes and gobbling up DNA.

Now multiple-drug resistant (MDR) microbes are rampaging across our world, trading plasmids, giving rise to more MDR microbes. They are most commonly found in hospitals; indeed, they are the causative agents for a large number of nosocomial (hospital-acquired) infections. Normally harmless bacteria that get along rather well with healthy people attack and thrive in the bodies of the very sick or the very young or old, whose immune systems are already overtaxed, common antibiotics no longer effective in combating these microorganisms.

Fortunately for us, our resources have not yet been exhausted in our race against microbes. There are reports claiming that stopping the use of a particular antibiotic will, over time, reverse the resistance to the antibiotic⁷. Microbes are parasites by nature and, like most other creatures on Earth (barring man), are highly adaptable. Those who inhabit other living creatures must make sure their hosts stay alive long enough for them (the microbes) to multiply and spread to other hosts. A microbe that kills off its host is not only ungrateful, it is not likely to have many descendants either⁸. Therefore, in nature’s own feedback loop, a microorganism will have inclination towards mild virulence. And in this case, in the absence of selective forces, the trend will eventually shift toward sensitive strains of microbes.

However, switching from drug to drug is no long-term solution to this problem, and should not be allowed to stand alone. To successfully fight antibiotics resistance, new classes of drugs must be developed or, at the very least, analogs of existing antibiotics must be found. The second approach will, needless to say, be much simpler, since it only involves synthesizing drugs that have the same mode of action as existing ones but do not possess the same weaknesses. The first approach (which would make Sissyphus think twice about his task) involves isolating new compounds or custom-making them in the lab to target specific parts of microorganisms. A number of these new experimental drugs are designed to inhibit protein synthesis in the bacterial cell, an example of which is the oxazolidinone family of drugs.

(It is somewhat ironic, however, that nature has taught us that if there’s anything that microorganisms are good at, it’s adapting to new environments. After all, they were here first.)

Pharmaceautical research and drug research must go hand-in-hand with education if we are ever to win this war against pestilence. The general public - and not just pharmacists and bacteriologists - must know at least the essential facts about antibiotics and the hazards of antibiotics misuse. They must learn that any weapon used too often and too much will inevitably, in the long run, turn against the one who wields it along with multitudes of innocents.

But is this enough? When does our war against antibiotics resistance - for it is the antibiotics resistance phenomenon and not bacteria that we are battling - end? The more anthropocentric of us may opine that we should get rid of the lot of them (bacteria) before they do us any more harm; others may say that we had it coming for messing around with nature’s delicate balance. Indeed, if we are to opt for eradication, we will be forced to get rid of all bacteria because we will claim that any given one is a potential threat to the survival of mankind. However, we have all coevolved and coexisted with microorganisms to the point that we can no longer get along without them synthesizing vitamins in our guts, or digesting cellulose in ruminant animals. Who is to say that even with increasingly developed and sophisticated technology we can find substitutes for this essential part of our lives?

There are three possible futures for mankind: (1) that we will eventually rid the earth of microorganisms, and live a life of sterile existence, depending heavily on massive quantities of synthesized vitamins and amino acids and other compounds that our bodies no longer have the ability to make; (2) that the wantonly indiscriminate usage of antibiotics and lack of awareness will send us plunging into another Dark Age, helpless to stave off the waves of bacterial infections that our medicines have become useless against, or (3) that mankind will eventually learn to manipulate the fine balance of nature and domesticate the microbes so that the useful ones become permanently fused to our lives and the harmful ones are removed of most of their potency, thus becoming more of a general inconvenience than health threat.

Which of these futures will become reality? As one person, we may only be able do to pitifully little; as one people, we may actually have enough momentum to push the destiny in our direction of choice.

Books you may be interested to read:

If you are interested in seeing the history of our world from a different point of view, read:

Margulis, L and D Sagan. 1986. Microcosmos: Four billion years of microbial evolution. University of California Press.

To know more about mankind’s struggle with pestilence, check out:

Brookesmith, P. 1997. Future plagues: Biohazard, disease and pestilence. Universal International Pty Ltd, Australia. (I got the history facts for this article from there)

If you are an aspiring microbiologist, or think that you would like to go into some branch of microbiology:

Madigan, MT, JM Martinko, and J Parker. 1997. Brock Biology of Microorganisms, 8th edition. Prentice Hall International. (There may be newer editions in the market by now)

If you’d like to know more about antibiotics:

Conte, JE, Jr. 1995. Manual of antibiotics and infectious disease, 8th ed. Williams and Wilkins, Baltimore.